Haemorheologic Enhancement of Cerebral Perfusion Improves Oxygen Supply and Reduces Aß Plaques Deposition in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a consequence of complex interactions of age-related neurodegeneration and vascular-associated pathologies, affecting more than 44 million people worldwide. For the last decade, it has been suggested that chronic brain hypoperfusion and consequent hypoxia play a direct role in the pathogenesis of AD. However, current treatments of AD have not focused on restoring or improving microvascular perfusion. In a previous study, we showed that drag reducing polymers (DRP) enhance cerebral blood flow and tissue oxygenation. We hypothesised that haemorheologic enhancement of cerebral perfusion by DRP would be useful for treating Alzheimer's disease. We used double transgenic B6C3-Tg(APPswe, PSEN1dE9) 85Dbo/Mmjax AD mice. DRP or vehicle (saline) was i.v. injected every week starting at four months of age till 12 months of age (10 mice/group). In-vivo 2-photon laser scanning microscopy was used to evaluate amyloid plaques development, cerebral microcirculation, and tissue oxygen supply/metabolic status (NADH autofluorescence). The imaging sessions were repeated once a month till 12 months of age. Statistical analyses were done by independent Student's t-test or Kolmogorov-Smirnov tests where appropriate. Differences between groups and time were determined using a two-way repeated measures ANOVA analysis for multiple comparisons and post hoc testing using the Mann-Whitney U test. In the vehicle group, numerous plaques completely formed in the cortex by nine months of age. The development of plaques accumulation was accompanied by cerebral microcirculation disturbances, reduction in tissue oxygen supply and metabolic impairment (NADH increase). DRP mitigated microcirculation and tissue oxygen supply reduction - microvascular perfusion was 29.5 ± 5%, and tissue oxygen supply was 22 ± 4% higher than in the vehicle group (p < 0.05). In the DRP group, amyloid plaques deposition was substantially less than in the vehicle group (p < 0.05). Thus, rheological enhancement of blood flow by DRP is associated with reduced rate of beta amyloid plaques deposition in AD mice.

Drag-Reducing Polymers Improve Vascular Hemodynamics and Tissue Oxygen Supply in Mouse Model of Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic metabolic disease characterised by hyperglycaemia and glucose intolerance caused by impaired insulin action and/or defective insulin secretion. Long-term hyperglycaemia leads to various structural and functional microvascular changes within multiple tissues, including the brain, which involves blood-brain barrier alteration, inflammation and neuronal dysfunction. We have shown previously that drag-reducing polymers (DRP) improve microcirculation and tissue oxygen supply, thereby reducing neurologic impairment in different rat models of brain injury. We hypothesised that DRP could improve cerebral and skin microcirculation in the situation of progressive microangiopathies associated with diabetes using a mouse model of diabetes mellitus. Diabetes was induced in C57BL/6 J mice with five daily consecutive intraperitoneal injections of streptozotocin (50 mg/kg/day). Animals with plasma glucose concentrations greater than 250 mg/dL were considered diabetic and were used in the study following four months of diabetes. DRP (2 ppm) was injected biweekly during the last two weeks of the experiment. Cortical and skin (ear) microvascular cerebral blood flow (mCBF) and tissue oxygen supply (NADH) were measured by two-photon laser scanning microscopy (2PLSM). Cerebrovascular reactivity (CVR) was evaluated by measuring changes in arteriolar diameters and NADH (tissue oxygen supply) during the hypercapnia test. Transient hypercapnia was induced by a 60-second increase of CO2 concentration in the inhalation mixture from 0% to 10%. Compared to non-diabetic animals, diabetic mice had a significant reduction in the density of functioning capillaries per mm3 (787 ± 52 vs. 449 ± 25), the linear velocity of blood flow (1.2 ± 0.31 vs. 0.54 ± 0.21 mm/sec), and the tissue oxygen supply (p < 0.05) in both brain and skin. DRP treatment was associated with a 50% increase in all three parameters (p < 0.05). According to the hypercapnia test, CVR was impaired in both diabetic groups but more preserved in DRP mice (p < 0.05). Our study in a diabetic mouse model has demonstrated the efficacy of hemorheological modulation of blood flow by DRP to achieve increased microcirculatory flows and tissue oxygen supply.

Resuscitation Fluid with Drag Reducing Polymer Enhances Cerebral Microcirculation and Tissue Oxygenation After Traumatic Brain Injury Complicated by Hemorrhagic Shock.

Traumatic brain injury (TBI) is frequently accompanied by hemorrhagic shock (HS) which significantly worsens morbidity and mortality. Existing resuscitation fluids (RF) for volume expansion inadequately mitigate impaired microvascular cerebral blood flow (mvCBF) and hypoxia after TBI/HS. We hypothesized that nanomolar quantities of drag reducing polymers in resuscitation fluid (DRP-RF), would improve mvCBF by rheological modulation of hemodynamics. METHODS: TBI was induced in rats by fluid percussion (1.5 atm, 50 ms) followed by controlled hemorrhage to a mean arterial pressure (MAP) = 40 mmHg. DRP-RF or lactated Ringer (LR-RF) was infused to MAP of 60 mmHg for 1 h (pre-hospital), followed by blood re-infusion to a MAP = 70 mmHg (hospital). Temperature, MAP, blood gases and electrolytes were monitored. In vivo 2-photon laser scanning microscopy was used to monitor microvascular blood flow, hypoxia (NADH) and necrosis (i.v. propidium iodide) for 5 h after TBI/HS followed by MRI for CBF and lesion volume. RESULTS: TBI/HS compromised brain microvascular flow leading to capillary microthrombosis, tissue hypoxia and neuronal necrosis. DRP-RF compared to LR-RF reduced microthrombosis, restored collapsed capillary flow and improved mvCBF (82 ± 9.7% vs. 62 ± 9.7%, respectively, p < 0.05, n = 10). DRP-RF vs LR-RF decreased tissue hypoxia (77 ± 8.2% vs. 60 ± 10.5%, p < 0.05), and neuronal necrosis (21 ± 7.2% vs. 36 ± 7.3%, respectively, p < 0.05). MRI showed reduced lesion volumes with DRP-RF. CONCLUSIONS: DRP-RF effectively restores mvCBF, reduces hypoxia and protects neurons compared to conventional volume expansion with LR-RF after TBI/HS.

Improvement of Impaired Cerebral Microcirculation Using Rheological Modulation by Drag-Reducing Polymers.

Nanomolar intravascular concentrations of drag-reducing polymers (DRP) have been shown to improve hemodynamics and survival in animal models of ischemic myocardium and limb, but the effects of DRP on the cerebral microcirculation have not yet been studied. We recently demonstrated that DRP enhance microvascular flow in normal rat brain and hypothesized that it would restore impaired microvascular perfusion and improve outcomes after focal ischemia and traumatic brain injury (TBI). We studied the effects of DRP (high molecular weight polyethylene oxide, 4000 kDa, i.v. at 2 µg/mL of blood) on microcirculation of the rat brain: (1) after permanent middle cerebral artery occlusion (pMCAO); and (2) after TBI induced by fluid percussion. Using in vivo two-photon laser scanning microscopy (2PLSM) over the parietal cortex of anesthetized rats we showed that both pMCAO and TBI resulted in progressive decrease in microvascular circulation, leading to tissue hypoxia (NADH increase) and increased blood brain barrier (BBB) degradation. DRP, injected post insult, increased blood volume flow in arterioles and red blood cell (RBC) flow velocity in capillaries mitigating capillary stasis, tissue hypoxia and BBB degradation, which improved neuronal survival (Fluoro-Jade B, 24 h) and neurologic outcome (Rotarod, 1 week). Improved microvascular perfusion by DRP may be effective in the treatment of ischemic stroke and TBI.

Menopausal status affects the susceptibility of stored RBCs to mechanical stress.

The mechanical fragility index (MFI) is an in vitro measure of sublethal injury to RBCs. In our previous experiments, we demonstrated that an increase in sublethal injury (increasing MFI) was a component of the RBC storage lesion, and that the MFI was significantly higher amongst the RBC units from male donors compared to pre-menopausal female donors during storage. It was hypothesized that hormonal or menstrual factors contributed to this difference. In this study, we found that RBC units donated by post-menopausal women demonstrated an MFI that was significantly higher than those donated by pre-menopausal women throughout storage.

The use of the mechanical fragility test in evaluating sublethal RBC injury during storage.

BACKGROUND: The mechanical fragility index (MFI) is an in vitro measurement of the extent of RBC sublethal injury. Sublethal injury might constitute a component of the RBC storage lesion, thus the MFI was determined serially during routine RBC storage. METHODS: Leucoreduced AS-5- and SAGM-preserved RBCs were stored under routine blood bank conditions. The mechanical fragility (MF) of each unit was serially measured during storage. RESULTS: For both AS-5 and SAGM units, male and female RBCs demonstrated statistically significant increases in the MFI during storage. The MFI was significantly lower in AS-5 units compared to SAGM units throughout storage. Female RBCs had significantly lower MFI vs. male RBCs in both AS-5 and SAGM units at all times. No significant differences in MFI were observed between ABO groups for both genders for AS-5 RBCs. CONCLUSIONS: The MF of RBCs increases during storage. Both gender and preservation solution influenced the MFI; however, the male:female MFI ratios were similar at all time-points and remained stable, suggesting that gender-based biological differences exist independent of storage solution. The MF could be a useful test for evaluating the effect of novel interventions intended to mitigate the susceptibility of RBCs to sublethal injury during storage.

Microhaemodynamics within the blade tip clearance of a centrifugal turbodynamic blood pump.

A persistent challenge facing the quantitative design of turbodynamic blood pumps is the great disparity of spatial scales between the primary and auxiliary flow paths. Fluid passages within journals and adjacent to the blade tips are often on the scale of several blood cells, confounding the application of macroscopic continuum models. Yet, precisely in these regions there exists the highest shear stress, which is most likely to cause cellular trauma. This disparity has motivated these microscopic studies to visualize the kinematics of the blood cells within the small clearances of a miniature turbodynamic blood pump. A transparent model of a miniature centrifugal pump having an adjustable tip clearance (50-200 microm) was prepared for direct optical visualization of the region between the impeller blade tip and the stationary housing. Synchronized images of the blood cells were obtained by a microscopic visualization system, consisting of an inverted microscope fitted with long-working-distance objective lens (40x), mercury lamp, and high-resolution charge-coupled device camera electronically triggered by the rotation of the impeller. Experiments with 7 microm fluorescent particles revealed the influence of the gap dimension on the trajectory across the blade thickness. The lateral component of velocity (perpendicular to the blade) was dramatically enhanced in the 50 microm gap compared with the 200 microm gap, thereby reducing the exposure time. Studies with diluted bovine blood (Ht = 0.5 per cent) showed that the concentration of cells traversing the gap is also reduced dramatically (30 per cent) as the blade tip clearance is reduced from 200 microm to 50 microm. These results motivate further investigation into the microfluidic phenomena responsible for cellular trauma within turbodynamic blood pumps.

Capacity for red blood cell aggregation is higher in athletic mammalian species than in sedentary species.

The purpose of this study was to show that two rheological parameters, red blood cell (RBC) sedimentation rate and apparent blood viscosity at low shear rate, characterizing the degree of RBC aggregation, correlate significantly with the maximal mass-specific rate of oxygen consumption or aerobic capacity (VO2max). Comparisons were made within two groups of similarly sized athletic and sedentary species: group 1, pronghorn antelope, dog, goat, and sheep; and group 2, horse and cow. The pronghorn antelope (Antilocapra americana) is one of the most athletic mammals, and we have obtained data on the rheological properties of blood from this species for the first time. The values of apparent viscosity at hematocrit = 40% and shear rate = 0.277 s-1 measured in a rotational viscometer were 59.5, 42.6, and 9.1 cP for antelope, dog, and sheep blood, respectively, and 55.3 and 11.5 cP for horse and cow blood, respectively. The viscosity values for antelope, dog, and sheep blood can be correlated with aerobic capacity: ln viscosity = 4.48-106.3 VO2(-1)max (r2 = 0.998; P < 0.05). The values of RBC sedimentation rate at hematocrit = 40% were 12.8, 7.0, and 0 mm/h for antelope, dog, and sheep blood, respectively, and 45.3 and 0.1 mm/h for horse and cow blood, respectively. Therefore, the data showed that the athletic species exhibit a consistently higher degree of RBC aggregation than do the corresponding nonathletic species.

Mechanisms of red blood cell trauma in assisted circulation. Rheologic similarities of red blood cell transformations due to natural aging and mechanical stress.

Clinical experience with circulatory support devices has typically shown alteration of patient blood rheology exhibited through increasing blood viscosity and decreasing erythrocyte deformability. Our hemorheologic studies have additionally shown a remarkable increase in red blood cell (RBC) aggregation in the blood of artificial heart patients as compared to healthy donors. These hemorheologic changes may be caused by mechanical trauma to RBCs. The authors hypothesize that the mechanical trauma process, from a rheologic point of view, could be analogous to an "accelerated" RBC aging process. The hypothesis was examined through in vivo and in vitro experiments on RBCs, age-separated on the basis of density, specifically to identify the rheologic similarities between aged and mechanically traumatized RBCs. Older RBCs demonstrated an increased mechanical fragility, a decreased deformability, and a increased ability to aggregate as compared to younger RBCs. RBCs exposed to mechanical stress demonstrated similar alterations in the same rheologic parameters. Our experiments have also shown that mechanical stress decreases the negative surface charge of RBCs as is known to occur in aged RBCs. Similarities found between the processes of RBC mechanical trauma and senescence enhance our understanding of mechanisms of subhemolytic trauma incurred in assisted circulation. This may improve the design and evaluation of future heart assist devices through minimizing shear induced blood trauma.

Plasma protective effect on red blood cells exposed to mechanical stress.

Hemodilution with plasma expanders is a widely applied practice during extracorporeal circulation and hemodialysis. Despite the immediate beneficial effects of hemodilution, such as reduction of blood viscosity and red blood cell (RBC) aggregation, elevation of blood flow in the microcirculation, etc., the dilution of plasma may cause some unfavorable effects on RBCs, amplifying the mechanical damage caused by circulatory assist devices. The authors investigated the effect of partial and total replacement of plasma on susceptibility of human and bovine RBCs to mechanical stress in vitro. Hemolysis was measured after the exposure of RBCs suspended in different media to similar mechanical stress. Experiments were performed at room temperature with control of osmolality and viscosity of the suspension media. The lowest hemolysis was obtained for RBCs suspended in serum, plasma, and albumin solutions. Hemolysis in PBS and Dextran suspensions was more than three times higher than that in plasma (p < 0.001). The protective effect depended upon protein concentration. Human RBCs were found to be significantly more sensitive to mechanical stress than bovine RBCs in all investigated suspension media (p < 0.005). Human RBCs from men suspended in plasma were found to be significantly (p < 0.05) more fragile than RBCs from women. The presence of even small amounts of plasma (such as 25%) in the suspension media significantly (p < 0.001) decreased hemolysis. However, a 30% replacement of plasma with PBS or Dextran solutions caused a statistically significant (p < 0.001) increase in mechanical hemolysis. This suggests that a decrease in the concentration of plasma proteins due to hemodilution may elevate blood damage during extracorporeal circulation and hemodialysis.

A sheep model for the study of hemorheology with assisted circulation. Effect of an axial flow blood pump.

Hemorheologic investigations were performed on nine sheep during the in vivo evaluation of a new axial flow ventricular assist device, the Nimbus AxiPump (Nimbus, Inc., Rancho Cordova, CA). Blood hematocrit, plasma and whole blood viscosity, red blood cell (RBC) deformability and aggregation, plasma fibrinogen, and free hemoglobin (hemolysis) levels were measured. Changes in the main rheologic parameters of sheep blood relative to the pre-implant values were minor and transient. The exception was RBC aggregation, which appeared on the third day of implantation. (Sheep blood does not normally demonstrate RBC aggregation.) Sheep RBCs started to form classic rouleaux typically on the third post-operative day simultaneously with increasing fibrinogen level. To investigate the relative effects of mechanical stress and elevated fibrinogen levels on RBC aggregability, in vitro studies were conducted with blood from control sheep. These studies indicated that neither mechanical trauma nor elevated fibrinogen alone caused RBC aggregation as seen in vivo. However, combined mechanical stress and elevated fibrinogen did cause this unusual effect for sheep blood.

Decrease in red blood cell deformability caused by hypothermia, hemodilution, and mechanical stress: factors related to cardiopulmonary bypass.

During extracorporeal circulation in cardiopulmonary bypass (CPB) surgery, blood is exposed to anomalous mechanical and environmental factors, such as high shear stress, turbulence, decreased oncotic pressure caused by dilution of plasma, and moderate and especially deep hypothermia widely applied during CPB in infants. These factors cause damage to the red blood cells (RBCs), which is manifest by immediate and delayed hemolysis and by changes in the mechanical properties of RBCs. These changes include, in particular, decrease in RBC deformability impeding the passage of RBCs through the microvessels and may contribute to the complications associated with CPB surgery. We investigated in vitro the independent and combined effects of hypothermia, plasma dilution, and mechanical stress on deformability of bovine RBCs. Our studies showed each of these factors to cause a significant decrease in the deformability of RBCs, especially acting synergistically. The impairment of RBC deformability caused by hypothermia was found to be more pronounced for RBCs suspended in phosphate buffered saline (PBS) than for RBCs suspended in plasma. The decrease in RBC deformability caused by mechanical stress was significantly exacerbated by dilution of plasma with PBS. In summary, results of our in vitro study strongly point to a possible detrimental consequence of conventional CPB arising from increased RBC rigidity, which may lead to impaired microcirculation and tissue oxygen supply.

Effect of perfluorochemical emulsion on blood trauma and hemorheology.

One of the major problems of development and improvement of heart assist devices is the reduction of blood cell damage. The extremely high levels of shear stress, turbulence, prolonged contact between blood and foreign surfaces, and other abnormal hydrodynamic circumstances have been shown to cause hemolysis, activation of platelets, and changes in mechanical properties of red blood cells. Hemolysis, in turn, can drastically increase red blood cell aggregation at low shear conditions. A new pharmacologic approach to reduce blood trauma and improve rheologic properties of blood subjected to mechanical stress was investigated. These experiments showed that the replacement of 20% of the plasma volume with Fluosol (Alpha Therapeutic Corp., Los Angeles, CA), a perfluorochemical that transports oxygen, reduced mechanical fragility of human (P < 0.01) and ovine (P = 0.054) red blood cells by approximately 30%. The same replacement of plasma with Fluosol reduced hemolysis (plasma free Hb) by approximately 40% compared to control (P < 0.05) during in vitro pumping of blood with a centrifugal pump. A 20% replacement of plasma volume with Fluosol remarkably reduced low shear blood viscosity (from 31.9 +/- 6.1 to 18.2 +/- 4.8 cP, for shear rate gamma = 0.277 sec-1) and erythrocyte sedimentation rate (from 16.7 +/- 9.2 to 3.1 +/- 3.1) mm/hr) in human blood. Decrease of these parameters indicates the reduction of red blood cell aggregation. Results of this study demonstrate the potential feasibility of Fluosol to improve mechanical properties of blood in patients with heart assist devices.

In vivo evaluation of the Nimbus axial flow ventricular assist system. Criteria and methods.

Continuing in vivo trials are being conducted at the University of Pittsburgh using the Nimbus axial flow blood pump (AxiPump). To date, 14 sheep experiments have been performed to address several issues related to short-term support. Six acute experiments (< 6 hr) have been performed to assess hemodynamics related to speed regulation and to determine anatomic placement of the pump and cannulae. Eight short-term survival studies lasting up to 6 days have been performed to evaluate biocompatibility and system reliability, and to establish clinical management protocols. The AxiPump has been used as a left ventricular assist device (LVAD), right ventricular assist device (RVAD), and biventricular assist device (BiVAD) with left ventricular and right atrial cannulation. The AxiPump has demonstrated the ability to assume complete support of either the pulmonary or systemic circulation, or both. We have determined that sufficient surgical access may be obtained through left lateral thoracotomy for both LVAD and RVAD insertion. In the absence of post operative anticoagulation therapy, we have detected subclinical renal cortical infarctions in 6 of 8 short-term animals. Thrombus deposition has been observed at the ventricular cannula tip in 4 of 8 cases--necessitating design changes. Two short-term experiments have been terminated because of bleeding--one due to inflow cannula obstruction and one due to cannula failure. Plasma free hemoglobin levels were all below 15 mg/dl, except for one case complicated by inflow obstruction.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic animal health assessment during axial ventricular assistance: importance of hemorheologic parameters.

Chronic testing of the Nimbus/UOP Axial Flow Pump was performed on 22 calves for periods of implantation ranging from 27 to 226 days (average, 74 days). The following parameters were measured: plasma free hemoglobin, blood and plasma viscosity, erythrocyte deformability and mechanical fragility, oxygen delivery index (ODI), blood cell counts, hematocrit, hemoglobin, blood urea nitrogen, creatinine, bilirubin, total protein, fibrinogen, and plasma osmolality. Most of the above parameters were stable during the full course of support. Compared with baseline, statistically significant differences during the entire period of implantation were only found in: hematocrit (p<0.001), hemoglobin (p<0.005), red blood cell (RBC) count (p<0.001), and whole blood viscosity (p<0.01). Plasma viscosity and ODI were mostly stable during the period of implantation. In some animals, an acute increase in fibrinogen concentration, plasma and blood viscosity, and a decrease in ODI were found to be early signs of the onset of infection. A small (10%) decrease in deformability of RBCs was found during the first 2 weeks after implantation. This alteration in RBC deformability was highly correlated (r = 0.793) with changes in total plasma protein concentration that fell more than 15% (p<0.001) during the same period. Mechanical fragility of RBCs was found to be slightly increased after implantation. Plasma free hemoglobin remained close to baseline level (p>0.2). After the first 2 weeks of the postoperative period, pump performing parameters for all animals were consistent and stable. In general, the Nimbus/UOP Axial Flow Pump demonstrated basic reliability and biocompatibility and did not produce significant alterations in the mechanical properties of blood or animal health status. The pump provided adequate hemodynamics and was well tolerated by the experimental animal for periods as long as 7.5 months. Monitoring rheologic parameters of blood is very helpful for evaluation of health during heart-assist device application.

Relationship of blood pressure and pump flow in an implantable centrifugal blood pump during hypertension.

The purpose of this study was to evaluate the real time relationship between pump flow and pump differential pressure (D-P) during experimentally induced hypertension (HT). Two calves (80 and 68 kg) were implanted with the EVA-HEART centrifugal blood pump (SunMedical Technology Research Corp., Nagano, Japan) under general anesthesia. Blood pressure (BP) in diastole was increased to 100 mm Hg by norepinephrine to simulate HT. Pump flow, D-P, ECG, and BP were measured at pump speeds of 1,800, 2,100, and 2,300 rpm. All data were separated into systole and diastole, and pump flow during HT was compared with normotensive (NT) conditions at respective pump speeds. Diastolic BP was increased to 99.3+/-4.1 mm Hg from 66.5+/-4.4 mm Hg (p<0.01). D-P in systole was under 40 mm Hg (range of change was 10 to 40 mm Hg) even during HT. During NT, the average systolic pump flow volume was 60% of the total pump flow. However, during HT, the average systolic pump flow was 100% of total pump flow volume, although the pump flow volume in systole during HT decreased (33.1+/-5.7 vs. 25.9+/-4.0 ml/systole, p<0.01). In diastole, the average flow volume through the pump was 19.6+/-6.9 ml/diastole during NT and -2.2+/-11.1 ml/diastole during HT (p<0.01). The change in pump flow volume due to HT, in diastole, was greater than the change in pump flow in systole at each pump speed (p<0.001). This study suggests that the decrease of mean pump flow during HT is mainly due to the decrease of the diastolic pump flow and, to a much lesser degree, systolic pump flow.

Continued development of the Nimbus/University of Pittsburgh (UOP) axial flow left ventricular assist system.

Nimbus and the University of Pittsburgh (UOP) have continued the development of a totally implanted axial flow blood pump under the National Institutes of Health (NIH) Innovative Ventricular Assist System (IVAS) program. This 62 cc device has an overall length of 84 mm and an outer diameter of 34.5 mm. The inner diameter of the blood pump is 12 mm. It is being designed to be a totally implanted permanent device. A key achievement during the past year was the completion of the Model 2 pump design. Ten of these pumps have been fabricated and are being used to conduct in vitro and in vivo experiments to evaluate the performance of different materials and hydraulic components. Efforts for optimizing the closed loop speed control have continued using mathematical modeling, computer simulations, and in vitro and in vivo testing. New hydraulic blade designs have been tested using computational fluid dynamics (CFD) and flow visualization. A second generation motor was designed with improved efficiency. To support the new motor, a new motor controller fabricated as a surface mount PC board has been completed. The program is now operating under a formal QA system.

Progress on development of the Nimbus-University of Pittsburgh axial flow left ventricular assist system.

Nimbus Inc. (Rancho Cordova, CA) and the University of Pittsburgh have completed the second year of development of a totally implanted axial flow blood pump under the National Institutes of Health Innovative Ventricular Assist System Program. The focus this year has been on completing pump hydraulic development and addressing the development of the other key system components. Having demonstrated satisfactory pump hydraulic and biocompatibility performance, pump development has focused on design features that improve pump manufacturability. A controller featuring full redundancy has been designed and is in the breadboard test phase. Initial printed circuit layout of this circuit has shown it to be appropriately sized at 5 x 6 cm to be compatible with implantation. A completely implantable system requires the use of a transcutaneous energy transformer system (TETS) and a diagnostic telemetry system. The TETS power circuitry has been redesigned incorporating an improved, more reliable operating topography. A telemetry circuit is undergoing characterization testing. Closed loop speed control algorithms are being tested in vitro and in vivo with good success. Eleven in vivo tests were conducted with durations from 1 to 195 days. Endurance pumps have passed the 6 month interval with minimal bearing wear. All aspects of the program continue to function under formal quality assurance.

Heparin effect on red blood cell aggregation.

We studied the effect of relatively high dosages of heparin (25-150 U/ml) on some rheological parameters of donor blood. It was found that heparin increased the erythrocyte sedimentation rate (ESR) and low shear blood viscosity at all concentrations studied. The increase of these parameters indicates an elevation in RBC aggregation. In all samples with a heparin concentration of 100 U/ml, the average ESR was increased by approximately 75% (p < 0.001); whole blood viscosity increased under shear rate, gamma = 0.277 sec-1, by approximately 30% (p < 0.001). Since bolus injection of heparin may result in transient high local concentration, these results suggest a possible additional adverse effect to the well known heparin effect on platelet aggregation.

Gender difference in rheologic properties of blood and risk of cardiovascular diseases.

According to official statistical data there is a significant difference between pre-menopausal women and age-matched men in morbidity and mortality from cardiac diseases and especially from myocardial infarction. There are several speculations regarding the nature of this phenomenon which have both supporting and refuting evidence. Our hypothesis was that due to regular physiologic bleeding, rheological properties of blood of pre-menopausal women are superior to those of men, and place such women at a lower risk of cardiovascular diseases than men in any age group. We believe that this difference in hemorheological properties is due to the reduced concentration of red blood cells (RBCs) and due to greater population of younger and less population of older RBCs in female blood. We studied mechanical properties of blood from 47 pre-menopausal women and 50 age-matched men. Compared to female blood, male blood had higher viscosity and RBC aggregation and lower RBC deformability. Oxygen Delivery Index, calculated as a ratio of hematocrit to blood viscosity, was found to be significantly lower in male blood. Decreased oxygen delivery along with increased RBC aggregation and decreased RBC deformability may contribute to the higher risk for the development of cardiovascular diseases. Regular blood donation may reduce hematocrit and blood viscosity, improve rheological properties of blood, and increase oxygen delivery in men.